Related Abstracts

Significance: Autoimmunity is a significant barrier to transplantation. Based on previous studies, it is apparent that there are separate genetic regions that control susceptibility to autoimmunity vs resistance to transplantation tolerance, but these have been difficult to isolate in polygenic models. We have recently established that B6.SLE123 mice, in which a lupus phenotype is conferred by 3 genetic regions, resist tolerance induction to islet transplants in absence of any pre-existing autoimmunity. Using this congenic model, we now further trace which genetic regions contribute to tolerance resistance and their mechanisms.

Methods: Single congenic B6.SLE1, B6.SLE2, and B6.SLE3 mice were made diabetic, transplanted with C3H islets, and treated with anti-CD45RB (100ug/day, days 0,1,3,5,7). Rejection was detemrined by two consecutive BG values > 250mg/dL. Evaluation of the alloresponse was measured via ex vivo and in vivo mixed lymphocyte reactions (MLRs). IL-6 production was assessed via ELISA. IL-6 signaling blockade was achieved by administering 500ug of anti-IL6R on days -3,-1,1,3 relative to transplant; blockade efficacy was evaluated via phosphoflow cytometry.

Conclusions: Analysis of minimal genetic regions from an autoimmune background demonstrate strong effects preventing transplantation tolerance. We relate the function of one of these regions in lupus to increased IL-6. IL-6 blockade may enhance organ engraftment in autoimmunity and lupus.